PROJECT SUMMARY There is a fundamental gap in our understanding of the reasons behind the high prevalence of obesity in Samoa, which is among the highest observed across the globe. Over 80% of Samoan adults are overweight or obese, with severe obesity reaching an alarming 33% in women in American Samoa. In a genome-wide association study we recently identified a novel missense variant (p.Arg457Gln, minor allele frequency 0.259) in CREB3 Regulatory Factor (CREBRF) that is highly associated with BMI, with an effect size greater than any known common BMI risk variant. The overall goal of this research project is to gain insight into the metabolic differences responsible for the excess weight gain associated with the CREBRF variant. Based on our observations that overexpression of the missense variant promotes lipid storage and reduces energy substrate oxidation (decreased mitochondrial respiration) in an adipocyte model, our hypothesis is that a lower resting metabolic rate (RMR) is involved. Supporting a relationship between low mitochondrial respiration and low RMR, we recently observed that lower skeletal muscle mitochondrial respiration is associated with lower RMR in African American women (AAW). In addition, we recently demonstrated lower intervention induced weight loss in AAW compared to Caucasian women due to a lower RMR, leading to lower energy requirements. Based on these observations, and the fact that the majority of genes known to contribute to human obesity do so primarily by influencing the central control of energy intake and/or expenditure, we propose to determine the role that energy expenditure (EE) and energy intake (EI) play in the increased obesity risk in the Samoan population associated with the CREBRF missense variant. Based on our long-term experience working with obesity and health risks in the Samoan population, combined with our extensive experience assessing energy and substrate metabolism, our research team is ideally positioned to conduct these studies. We propose a longitudinal study to define the impact of the variant on energy balance in human subjects with zero, one, or two copies of the risk allele to address the following three specific aims: 1) to determine the components of EE and substrate metabolism [RMR; TEF, thermic effect of food; total EE; RQ, substrate utilization; and PA, physical activity] using gold standard methods that include doubly-labeled water (DLW), indirect calorimetry, and objective activity monitoring; 2) to determine EI using the gold standard method of DLW intake balance technique; and 3) to determine the relationship between energy metabolism and weight gain by comparing the above energy metabolism parameters and weight gain over 24-36 months. In the applicants opinion the proposed studies will provide novel, and significant insight into the metabolic differences responsible for the excess weight gain in those with the CREBRF variant, which in turn plays a significant role in the extreme prevalence of obesity in Samoa. This research will advance the understanding, prevention, and appropriate treatment of obesity and heart diseases in this high risk population.